Flavonoids are a diverse group of plant-derived chemicals that are produced by various higher plants, which can be found in numerous food sources such as fruits, vegetables, legumes, and whole grains. Compounds in this class have shown a wide variety of biological activities such as anti-inflammatory, antibacterial, antifungal and anticancer activities. In particular, due to their structural and functional similarities to endogenous estrogens, flavonoids have attracted considerable interest as alternative estrogens, termed phytoestrogens, and extensively studied for their potential role in many estrogen-dependent diseases including breast cancer. In fact, numerous flavonoids have shown interesting pharmacological activities and inhibitory activities against aromatase enzyme.
Genistein (GEN) is the most abundant isoflavone in soybeans. Some researchers suggest that GEN may be responsible for the relatively low incidence of hormone-dependent breast cancer in certain regions with high consumption of soy foods. Indeed, GEN has been one of the most widely studied natural products and has shown a number of important biological activities in breast cancer biology. GEN displays moderate binding to estrogen receptors, as well as exhibiting antiproliferative activity in many can cell lines mediated by several mechanisms of action. Furthermore, it is known that GEN exerts many beneficial effects on endogenous estrogens on several tissues such as bone and cardiovascular system. In addition to estrogenic activities, GEN has also demonstrated a variety of other interesting biological activities. It exerts antioxidant activity and is a potent scavenger of hydrogen peroxide. In addition, GEN has shown inhibitory abilities against various enzymes involved in tumor development and growth such as protein tyrosine kinases, DNA topoisomerases, and protein kinase C (PKC). It has also shown to inhibit angiogenesis and induce apoptosis and cell cycle arrest in the G2-phase. While GEN is the most extensively studied flavonoid for its versatile biological activities, it has been reported to exert no or very weak aromatase inhibition.
Aromatase has been a particularly attractive target for inhibition in the treatment of hormone-dependent breast cancer since the aromatization is the last step in steroid biosynthesis and is the rate-limiting step for estrogen synthesis. In general, however, isoflavones are considered less effective than flavones or flavonones in terms of aromatase inhibition. For this reason, to the best of our knowledge, there has been no medicinal chemistry effort to develop isoflavones-based aromatase inhibitors.